Abstract
In a recent randomized phase III clinical trial in metastatic colorectal cancer patients, the addition of the anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) cetuximab to bevacizumab and chemotherapy resulted in decreased progression-free survival, in particular for patients with the high-affinity FcγRIIIA. The presence of natural killer (NK) cells and type 2 (M2) macrophages in colorectal cancer was determined by immunohistochemistry, using antibodies to lineage-specific markers NKp46 and CD68 with CD163, respectively. Influence of tumor-bound cetuximab on M2 macrophages was carried out in vitro with EGFR-expressing tumor cells and short-term differentiated monocytes from blood donors, who were typed for the FcγRIIIA polymorphism (CD16). Antibody-dependent cellular cytotoxicity by NK cells is generally proposed as one of the antitumor mechanisms of mAbs. We found that CD163-positive M2 macrophages are much more abundant in colorectal carcinomas. In vitro analysis of M2 macrophages revealed high levels of Fc-gamma receptors (FcγR) and PD-L1 and production of IL-10 and VEGF but not IL-12. These anti-inflammatory and tumor-promoting mediators were released upon coculture with EGFR-positive tumor cells loaded with low concentrations of cetuximab. Macrophage activation depended on EGFR expression on the tumor cells, FcγRs, target specificity of the mAb and mobility of antibody complexes. Cetuximab-induced macrophage responses were more pronounced for FCGR3A 158-Val (high-affinity) carriers. These results suggest that tumor-promoting M2 macrophages are activated by the therapeutic mAb cetuximab in the local tumor microenvironment and argue that this immune mechanism should be taken into account for the application of therapeutic antibodies.
Highlights
Monoclonal antibodies have become important agents for the treatment of many types of malignancies
We show that macrophages with type 2 (M2) differentiation profile are abundantly present in colorectal carcinomas, much more than antibody-dependent cellular cytotoxicity– mediating natural killer cells
Colon carcinomas are heavily infiltrated with M2 macrophages but not with natural killer (NK) cells
Summary
Monoclonal antibodies (mAb) have become important agents for the treatment of many types of malignancies. Their principal mechanism of action is blocking growth factor pathways that are essential for tumor growth and progression. All clinically applied mAbs contain the Fc region of human IgG, which efficiently mediates activation through Fcg receptors (FcgR) on several types of immune cells. These IgG-binding receptors contribute to the clinical effect of mAbs, in addition to their direct inhibition on tumor growth [1]. The high-affinity valine allele has been associated with increased clinical response and survival in these studies, which is in line with in vitro studies indicating that antibody-dependent cellular cytotoxicity (ADCC) is more extensive for this allele [5]
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